UPDATE 2-FDA reviewers say Titan drug dose may be insufficient

* Review comes ahead of advisory committee meeting on
Thursday

* Probuphine is experimental drug to treat opioid addiction

* Titan stock down 41 pct at $1.20 in over-the-counter trade

By Toni Clarke

March 19 Titan Pharmaceuticals Inc's
experimental drug to treat opioid addiction was less effective
in a clinical trial than might have been expected, suggesting
the proposed dose could be too low, reviewers for the U.S. Food
and Drug Administration said in documents published on Tuesday.

The commentary was published on the FDA's website ahead of
an advisory panel meeting to be held on Thursday and sent the
company's stock down 41 percent to $1.20 in over-the counter
trading at midday on Tuesday.

The reviewers said they would ask the advisory panel whether
Titan should explore dosing further before the drug, Probuphine,
is approved.

Probuphine is a long-acting version of buprenorphine, a drug
sold by Britain's Reckitt-Benckiser Group Plc under the
brand names Subutex and Suboxone.

Unlike Subutex and Suboxone, which are dissolved daily under
the tongue, Titan's drug is implanted under the skin of the
upper arm during a 10-15-minute office procedure and delivers a
continuous supply of buprenorphine for six months.

Clinical data shows Probuphine to be more effective than
placebo in curbing addiction, but the results were still not
particularly robust, the reviewers said.

Only 8 percent of patients provided opioid-negative urine
samples for at least 80 percent of tests, while roughly a
quarter of Probuphine-treated patients were unable to provide
four opioid-negative samples over the course of six months, the
reviewers said.

"While the placebo group had even more discouraging results,
supporting the conclusion that Probuphine does have an effect on
drug use, overall, the response was not what one might hope for
given that the product ensures compliance with the medication
for six months," the reviewers said. "It prompts speculation
that the dose is simply not high enough."

Drug overdose death rates have more than tripled since 1990,
according to federal data. In 2008, more than 36,000 people died
from an overdose, mostly caused by opioid painkillers, which
outpaced deaths from heroin and cocaine combined.

ADDITIONAL SAFETY CONCERN

While the safety of Probuphine appears largely in keeping
with that of other buprenorphine products, it presents an
additional safety concern, reviewers said. It must be implanted,
potentially leading to surgery-related complications. They said
the product is in some ways similar to Norplant, an implantable,
progestin-releasing contraceptive which is no longer marketed in
the United States.

Even though insertion and removal of Norplant was performed
by trained healthcare providers, there were cases of
implantation and removal-related complications, some with
disabling consequences, the reviewers said. They will ask the
advisory committee whether it believes the company has
adequately addressed these concerns under its proposed risk
mitigation plan and whether the drug's benefit is enough to
outweigh the potential risks.

In December, Titan licensed the U.S. and Canadian rights to
Probuphine to Braeburn Pharmaceuticals, a company owned by the
venture capital firm Apple Tree Partners. Titan received an
up-front payment of $15.75 million and will receive up to $50
million if Probuphine is approved.

Reviewers noted that the dose of buprenorphine delivered by
four Probuphine implants is less than a third of the dose
delivered buprenorphine tablets.

"Potentially, Probuphine could deliver just enough
buprenorphine to allow patients to continue to use illicit
opioids without experiencing withdrawal when they stop," the
reviewers said.

RECKITT DOMINANCE

To date, the market for buprenorphine has been dominated by
Reckitt, a consumer goods company whose products range from
cleaning supplies to condoms. Subutex and Suboxone generated
sales in 2012 of roughly $1.3 billion.

Suboxone and Subutex lost market exclusivity in 2009, and
while generic competitors promptly introduced cheap copies of
Subutex they were slow to develop alternatives to Suboxone. In
the meantime, Reckitt persuaded many physicians to switch from
Suboxone tablets to Suboxone Film, its newer, patent-protected
wafer-like strip that patients dissolve under the tongue. At the
end of 2012, according to Reckitt, Suboxone Film had captured 64
percent of the market.

Even as it switched patients to Suboxone Film, Reckitt
aggressively fought to block generic competition to Suboxone
tablets. In a move generic drug critics claimed was designed to
thwart competition, Reckitt produced a report showing that
children were eight times more likely to be accidentally exposed
to Suboxone tablets than to Suboxone Film.

It petitioned the FDA to reject all generic versions of
Suboxone tablets unless packaging safety standards were
improved. The company said it could not ignore the danger posed
by the tablets it had been selling for a decade, and in
September said it would only sell Suboxone Film.

The FDA rejected Reckitt's petition, saying there was not
enough evidence to support the need for stricter packaging
rules. And it expressed skepticism over Reckitt's motives,
saying the timing of its decision to stop marketing the tablet,
"given its close alignment with the period in which generic
competition for this product was expected to begin," could not
be ignored.

Earlier this year the FDA approved generic versions of
Suboxone tablets from Amneal Pharmaceuticals LLC and Actavis Inc
.

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